A number of different protein families share a conserved domain known as the calcium-dependent carbohydrate recognition domain. This domain is also known as the C-type lectin domain, because it was originally identified in carbohydrate binding proteins, called lectins, found in plants. The C-type lectin domain is a stretch of 110-130 amino acids, containing four conserved cysteine residues in two disulfide bonds, as well as a number of other conserved residues. The domain mediates the calcium-dependent binding of certain carbohydrate residues on glycoproteins. Several categories of proteins contain C-type lectin domains, including Type-II membrane proteins such as the asialoglycoprotein receptor, collectins such as the pulmonary surfactant-associated protein, selectins such as the endothelial leukocyte adhesion molecule-1 (ELAM-1), Type-I membrane proteins such as macrophage mannose receptor, and many others. (Drickamer, K. J. (1988) J. Biol. Chem. 263:9557-9560; PROSITE document PDOC00537).
One group of cell-surface receptor proteins that share the C-type lectin domain as well as certain other structural features. These receptors possess a short N-terminal cytosolic region, a single transmembrane-spanning region, and a large extracellular C-terminal region containing the C-type lectin domain. Examples of these proteins include the macrophage C-type lectin receptor, rat Kupffer cell receptor, B cell low affinity IgE receptor, natural killer cell receptors P1(NKR-P1) and CD94, and the oxidized low-density lipoprotein (LDL) receptor. (Sawamura, T. et al. (1997) Nature 386:73-77).
NKR-P1 and CD94 are proteins expressed on the surface of natural killer T (NK) cells. They recognize and bind major histocompatibility complex (MHC) Class I molecules. This target-recognition step is followed by activation of the NK cell, and eventual destruction of the target cell. The receptor for oxidized LDL (OXLDL) shares significant sequence similarity with NKR-P1. OXLDL binds and internalizes oxidized low-density lipoprotein, a carrier molecule for cholesterol. (Sawamura, supra; Nagase, M et al. (1997) Biochem. Biophys. Res. Comm. 237:496-498)
Cholesterol is an essential component in membrane biosynthesis. Cholesterol serves as a building block in the synthetic pathways for numerous steroid hormones, bile salts, and other important biologically active compounds. In addition, the role of elevated cholesterol levels in atherosclerosis, hypertension, and coronary artery disease is well established.
Cholesterol is transported in the blood as a complex of cholesterol, cholesteryl ester, phospholipid, and specific proteins. Based on the identity of the proteins and the relative composition of the other components, this complex is called either high-density lipoprotein (HDL), low-density lipoprotein (LDL), or intermediate-density lipoprotein (IDL). High plasma concentrations of LDL and low plasma concentrations of HDL are clearly associated with increased incidence of arteriosclerosis and hypertension. Some of the deleterious effects of LDL may be associated with an oxidized derivative of LDL. Exposure of LDL to oxidizing agents like copper or iron results in peroxidation of the lipid components, and covalent modifications of the protein components, of LDL. The uptake and subsequent degradation of OXLDL in vascular endothelial cells have been implicated in the genesis of atherosclerotic plaques. Thus, OXLDL may play a role in the pathogenesis of atherosclerosis. (Hajjar, D. P., and Haberland, M. E. (1997) J. Biol. Chem. 272:22975-22978).
The discovery of a new human oxidized LDL receptor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of cancer, autoimmune disorders, and cardiovascular disorders.